(1) Field of the Invention
The present invention involves the preparation of 5-hydroxymethyl-2-oxazolidinone 1 from a novel cyclic boronic acid ester of 3-4-dihydroxy butyramide. The starting ester have the formula: ##STR1##
where R is a non-interfering group. The preferred oxazolidinone has the formula: ##STR2##
(2) Description of Related Art
Optically pure-5-hydroxymethyl-oxazolidinones can be obtained by carbonylation of 3-amino-1,2-dihydroxypropane (3-amino-1,2-propanediol) with reagents such as phosgene, ethyl chloroformate and carbonyl imidazole. It is also possible to perform this carbonylation reaction electrochemically. In any event, a way of preparing the optically active amino-diol has to be devised and a carbonylation step has to be performed.
General methods for the synthesis of oxazolidinones from vicinal amino alcohols:
1. Catalytic oxidation--Bartolo Gabriele, Giuseppe Salerno, Donatella Brindisi, Mirco Costa, and Gian Paolo Chiusoli, Organic Letters 625-627 (2000)--"Synthesis of 2-oxazolidinones by Direct Palladium-Catalyzed Oxidative Carbonylation of 2-Amino-1-alkanols";
2. Diethylcarbonate--Danielmeier, K.; Steckhan E.--"Efficient Pathways to (R)-5-hydroxymethyl-2-oxazolidinone and (S)-5-hydroxymethyl-2-oxazolidinone and some derivatives", Tetrahedron-Asymmetr 6: (5) 1181-1190 (May 1995);
3. Carbonyldiimidazole--Warmerdam EGJC, Brussee J., Vandergen A., Kruse, C. G., "Synthesis of (R)-5-(hydroxymethyl)-3-isopropyloxazolidin-2-one and (S)-5-(Hydroxymethyl)-3-isopropyloxazolidin-2-one, Intermediates in the preparation of optically-active beta-blockers", Helv Chim Acta 77: (1) 252--256 (1994); 4. Eckert, H., Forster, B., "Triphosgene, A crystalline phosgene substitute", Angew. Chem. Int. Ed. 26: (9) 894-895 (Sept 1987); and Seneci, P., Caspani, M., Ripamonti F., Ciabatti, R., "Synthesis and Antimicrobial Activity of Oxazolidin-2-ones and Related Heterocycles", J. Chem. Soc. Perk T 1 (16) 2345-2351 (Aug. 21, 1994).
Oxazolidinones have emerged as a very important class of compounds in drug development especially in the areas of antimicrobials (Diekema, D. J., et al., Drugs 59 7-16 (2000)) and behavioral disorders (Brenner, R., et al., Clin. Therapeut. 22 4 411-419 (2000)). They are especially active against some of the most resistant human pathogens including vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, cephalosporin-resistant Streptococcus pneumoniae and several organisms that display penicillin resistance (Diekema, D. J., et al., Drugs 59 7-16 (2000)). Linezolid, having the formula hereinafter, was recently recommended for approval for the treatment of infections from antibiotic resistant bacterial strains especially those that are resistant to vancomycin. ##STR3##
Optically active 3, 4-dihydroxybutyric acid and 3-hydroxy-y-lactones are important sources, of chirality. They can be obtained in commercial quantities from carbohydrates such as starch, lactose, maltodextrins, cellulose and arabinose by oxidative degradation (Hollingsworth, R. I. Biotechnology Annual Review 2 281-291 (1996); Hollingsworth, R. I., J. Org. Chem. 64 7633-7634 (1999)). See also U.S. Pat. Nos. 5,292,939, 5,808,107, 5,319,110 and 5,374,773 to Hollingsworth. Although 3,4-dihydroxybutramide can be readily prepared from the acids and lactones, the amides cannot be subjected directly to Hofmann reaction because of interference by the 4-hydroxyl group.
The present invention provides a way of masking and then un-masking this group. A method of doing this in which the unmasking takes place during the transformation is very valuable. This is achieved here using boronic acid esters.